Herpes viruses inflict a wide range of diseases against humans and animals. For instance; herpes simplex viruses, types 1 and 2 (HSV-1 and HSV-2), are responsible for cold sores and genital lesions, respectively; varicella zoster virus (VZV) causes chicken pox and shingles; and the Epstein-Barr virus (EBV) causes infectious mononucleosis.
Over the past two decades, a class of compounds known as the purine and pyrimidine nucleoside analogs has received the most attention by investigators in the search for new therapeutic agents for treatment of herpes virus infections. As a result, several nucleoside analogs have been developed as antiviral agents. The most successful to date is acyclovir which is the agent of choice for treating genital herpes simplex infections.
Nevertheless, in spite of some significant advances, the need for effective, safe therapeutic agents for treating herpes viral infections continues to exist. For a review of current therapeutic agents in this area, see M. C. Nahata, "Antiviral Drugs: Pharmacokinetics, Adverse Effects and Therapeutic Use", J. Pharm. Technol., 3, 100 (1987).
The present application discloses a group of peptide derivatives having activity against herpes viruses. The selective action of these peptides against herpes viruses, combined with a wide margin of safety, renders the peptides as desirable agents for combating herpes infections.
The following references disclose peptides or peptide derivatives which have been associated with anti-herpes activity:
B. M. Dutia et al., Nature, 321, 439 (1986), PA0 E. A. Cohen et al., Nature, 321, 441 (1986), PA0 J. H. Subak-Sharpe et al., UK patent application 2185024, published Jul. 8, 1987, PA0 P. Gaudreau et al., J. Biol. Chem., 262, 12413 (1987), PA0 E. A. Cohen et al., U.S. Pat. No. 4,795,740, Jan. 3, 1989, PA0 R. Freidinger et al., U.S. Pat. No. 4,814,432, Mar. 21, 1989, PA0 V. M. Garskey et al., U.S. Pat. No. 4,837,304, Jun. 6, 1989, PA0 R. Colonno et al., U.S. Pat. No. 4,845,195, July 4, 1989, PA0 P. Gaudreau et al., J. Med. Chem., 33, 723 (1990), PA0 J. Adams et al., European patent application 408,973, published Jan. 23, 1991, PA0 P. L. Beaulieu et al., European patent application 411,332, published Feb. 6, 1991, PA0 J. Adams et al., European patent application 411,333, published Feb. 6, 1991, PA0 J. Adams et al., European patent application 411,334, published Feb. 6, 1991, PA0 R. L. Tolman et al., European patent application 412, 595, published Feb. 13, 1991, PA0 W. T. Ashton et al., European patent application 438,873, published Jul. 31, 1991, PA0 P. L. Beaulieu et al., European patent application 461,546, published Dec. 18, 1991, PA0 P. Gaudreau et al., J. Med. Chem., 35, 346 (1992), PA0 R. Deziel and Y. Guindon, Canadian patent application 2,033,448, published Jul. 1, 1992, and L. L. Chang et al., Biorganic & Medicinal Chemistry Letters, 2, 1207 (1992).
The subject peptides of the previous reports can be distinguished from the peptides of the present application by characteristic structural and biological differences.
Abbreviations and symbols used hereinafter are defined in the "Details of the Invention" section of this application.